We have synthesized a large variety of test-tube systems which simulate the enzyme-substrate complex by having the substrate frozen into a single, very favorable conformation and by having the interacting groups brought into the closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions at rates approaching those catalyzed by enzymes (but independently of any functional assistance). Recent work has involved a study of steric and electronic effects on NMR and IR spectra across tight space rather than through covalent bonds. These results simulate the spectral perturbations to be expected in a tight ES complex. The upper limit of energy-related steric crowding could not be evaluated, however, because of inability to introduce the very bulky iodo group. After considerable effort, this goal has been reached and we are now attempting to introduce the trifluoromethyl group, the last of the bulky substituents planned for the present series. As part of our studies of practical applications of stereopopulation control, we have been exploring the use of various derivatives of biogenic amines and antibiotics as prodrugs. The intent is to facilitate transport from the gut to the circulatory system to the brain by temporary masking of charge within the molecule, by improvement in lipophilicity and by regeneration based simply on local pH variation in receptor sites or on local concentrations of potent reducing agents. Studies with o- nitrophenylpropionic acid as potential "Pro-ProDrugs" have made significant headway with the completion of the parent derivatizing groups. To date, these carriers have been coupled to benzylamine, GABA methyl ester, and a protected DOPA derivative. Preliminary kinetic investigations have shown that chemical reduction of the nitro group occurs easily in both series and at the same rate, while cyclization to the lactam (with release of the group on the acyl carbon) is indeed hastened by the presence of the gem-dimethyl group on the alpha carbon.